JMJD6 promotes hepatocellular carcinoma carcinogenesis by targeting CDK4

Abstract

Jumonji domain-containing protein 6 (JMJD6), a histone arginine demethylase, plays a multifaceted and significant role in embryonic development and cancer progression. However, the function of JMJD6 and its precise mechanism in regulating hepatocellular carcinoma (HCC) remain unknown. Here, we show that aberrant JMJD6 overexpression is associated with poor prognosis and aggressive characteristics of HCC. In hepatoma cell lines, we demonstrated that knockdown of JMJD6 inhibited hepatoma cell migration and proliferation. JMJD6 overexpression displays the opposite effects. Interestingly, JMJD6 regulates hepatoma cell cycle and apoptosis progression. Moreover, there was a positive correlation between cell cycle regulatory protein CDK4 and JMJD6 level. Mechanism analysis suggested JMJD6 promotes CDK4 expression by directly targeting to its promoter, and interacts with PCAF to regulate the histone modifications on the promoter of CDK4. Furthermore, we found that inhibiting CDK4 abolished the ability of JMJD6 in enhancing cell proliferation. Taken together, for the first, we demonstrated that JMJD6 is critically involved in HCC carcinogenesis, and indicated that JMJD6 may be a novel potential biomarker for HCC.

Functions and mechanisms of lysine crotonylation

“…Cancer is a life-threatening malignancy that has become a global healthcare problem. [48][49][50] Using immunohistochemical methods, we recently reported that levels of crotonylation in eight types of cancer. 51 We found the expression level of crotonylation was down-regulated in liver, stomach and kidney carcinomas, and up-regulated in thyroid, oesophagus, colon, pancreas and lung carcinomas, suggesting that crotonylation may modulate different cancer progression.…”

Jumonji domain‐containing protein 6 protein and its role in cancer

“…Aberrant CDK4 expression may result in increased proliferation, which is frequently observed in many types of cancer, including breast cancer, hepatocellular cancer and melanoma . JMJD6 promotes CDK4 expression by suppressing H4R3me 2(s) binding on the CDK4 promoter . Furthermore, JMJD6 interacts with p300/CBP‐associated factor (PCAF), a member of the GCN5‐related N‐acetyl transferase (GNAT) family of protein acetyltransferases, to regulate the histone modifications on the CDK4 promoter .…”

“…17 Overexpression of JMJD6 reduces the apoptosis of human hepatoma-derived cell lines. 17 The JMJD6 expression level is significantly increased in human hepatocellular carcinoma tissues than in normal liver tissues. 17 JMJD6 protein level in hepatocellular carcinoma is positively correlated with histological grade, and the JMJD6 mRNA level is significantly correlated with tumour grade and TNM stage.…”

“…[118][119][120][121] promotes CDK4 expression by suppressing H4R3me 2(s) binding on the CDK4 promoter. 17 Furthermore, JMJD6 interacts with p300/ CBP-associated factor (PCAF), a member of the GCN5-related N-acetyl transferase (GNAT) family of protein acetyltransferases, to regulate the histone modifications on the CDK4 promoter. 17 The evidence suggesting that CDK4 is a necessary downstream effector of JMJD6 in regulating hepatoma cell proliferation also comes from the observations that the ability of JMJD6 to promote cancer cell proliferation can be abolished by inhibiting CDK4.…”

“…13,14 Overexpression of JMJD6 is correlated with advanced clinicopathological stage, increased aggressiveness and poor survival. 12,[15][16][17] Here, we summarized the structure and functions of JMJD6 based on relevant basic researches. In particular, we focused on the role of JMJD6 in cancer progression and candidate mechanisms in order to highlight that JMJD6 may represent an attractive target for a new generation of anticancer drugs.…”